EP3638686B1 - Peptidyl-cétoamides utilisés en tant qu'inhibiteurs de protéases rohomboïdes - Google Patents

Peptidyl-cétoamides utilisés en tant qu'inhibiteurs de protéases rohomboïdes Download PDF

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EP3638686B1
EP3638686B1 EP18734418.9A EP18734418A EP3638686B1 EP 3638686 B1 EP3638686 B1 EP 3638686B1 EP 18734418 A EP18734418 A EP 18734418A EP 3638686 B1 EP3638686 B1 EP 3638686B1
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arg
compound
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group
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EP3638686A1 (fr
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Kvido STRISOVSKY
Pavel Majer
Stanco STANCEV
Anezka TICHA
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Institute of Organic Chemistry and Biochemistry CAS
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    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
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    • C07K5/1019—Tetrapeptides with the first amino acid being basic
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
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    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
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    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to a class of chemical compounds, compositions comprising such compounds, methods for their synthesis, and their use in the therapy of various maladies.
  • Rhomboid intramembrane proteases (EC 3.4.21.105, Pfam PF01694) are evolutionarily widespread and fulfil important biological functions including growth factor secretion, regulation of mitochondrial dynamics, and membrane protein quality control. They are increasingly being explored as potential drug targets, for example for malaria (Baker et al., 2006, Lin et al., 2013, O'Donnell et al., 2006), cancer (Song et al., 2015), Parkinson's disease (Meissner et al., 2015), diabetes (Chan et al., 2013) and potentially for the control of infections by extraintestinal pathogenic Escherichia coli or related bacteria (Russell et al., 2017). In contrast to the promising roles of rhomboid proteases in disease contexts, selective and potent rhomboid inhibitors that could serve for cell biological studies, validation of therapeutic potential of rhomboids and as templates for drug development, are lacking.
  • Isocoumarins (Vosyka et al., 2013) are irreversible inhibitors, are reactive towards many other serine hydrolases (Bachovchin et al., 2014) and thus lack selectivity for rhomboids.
  • ⁇ -lactams are not very active in vivo (EC 50 -5-10 ⁇ M) (Pierrat et al., 2011), ⁇ -lactones are not very potent (apparent IC50 of ⁇ 40 ⁇ M) (Wolf et al., 2013), and both are slowly turned over by the enzyme.
  • a rational strategy to modulate selectivity for rhomboids is not available.
  • Rhomboids are serine proteases with a Ser-His catalytic dyad (Wang et al., 2006), and recognise their transmembrane substrates in a two-tier process. It is assumed that first a portion of the transmembrane domain of the substrate docks into an intramembrane interaction site of rhomboid within the plane of the lipid bilayer, upon which a linear segment of the substrate interacts with the water-exposed active site (reviewed in Strisovsky, 2013, Strisovsky, 2016).
  • This 'recognition motif' encompasses the P4 to P2' residues of the substrate (Strisovsky et al., 2009), it largely determines the k cat of the reaction (Dickey et al., 2013) and thus modulates selectivity towards a given rhomboid protease (Ticha et al., 2017).
  • peptidyl chloromethylketones Zoll et al., 2014
  • peptidyl aldehydes Cho et al., 2016
  • these classes of compounds lack selectivity and their potency is insufficient for their use as research tools.
  • novel potent and selective rhomboid inhibitors based on a modular scaffold of sequence-optimised peptidyl-ketoamide substituted with large hydrophobic substituent.
  • the inhibitors disclosed are useful in the treatment of a variety of indications associated with rhomboid proteases, for example, malaria, Parkinson's disease and cancer.
  • the invention provides compounds of the formula (II) wherein R1 is selected from the group consisting of H, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, each optionally substituted with from 1 to 3 substituents independently selected from the group consisting of alkyl, cyano, halo, oxo, nitro, hydroxyl, -O(alkyl), -NH 2 , -N(H)(alkyl), -N(alkyl) 2 , -S(alkyl), -S(O)(alkyl), -SO 2 alkyl, -NHCONH 2 , - CO 2 H, -CO 2 (alkyl),
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (II) together with a pharmaceutically acceptable excipient.
  • the invention provides a compound of formula (II) or a composition according to the second aspect for use in therapy.
  • the invention provides a compound of formula (II) or a pharmaceutical composition according to the second aspect for use in the treatment of a condition selected from malaria, cancer, Parkinson's disease, diabetes, and bacterial infection.
  • potent and selective covalent reversible inhibitors of rhomboid intramembrane proteases being peptidyl-ketoamides of the general formula (II).
  • the molecules comprise two moieties; the first is a peptidyl part, and the second is the tail substituent at the ketoamide nitrogen.
  • R2 is hydrogen
  • R1 is selected from the group consisting of alkyl, cycloalkyl, arylalkyl optionally substituted on the aryl ring with from 1 to 3 C1-C3 alkyl substituents, and alkoxycarbonylalkyl.
  • R1 is alkyl. More preferably, R1 is C1-C6 alkyl. More preferably, R1 is isopropyl, pentyl or pivaloyl.
  • R1 is cycloalkyl. More preferably, R1 is C3-C7 cycloalkyl. Still more preferably, R1 is cyclohexyl.
  • R1 is arylalkyl. More preferably, R1 is phenylalkyl or naphthylalkyl. Still more preferably, R1 is phenyl(C1-C6)alkyl. In such embodiments, the aryl moiety may optionally be substituted with from 1 to 3 substituents independently selected from C 1 -C 3 alkyl, halogen, C 1 -C 3 haloalkyl and C 1 -C 3 alkoxy; methyl is preferred.
  • Explicitly preferred groups R 1 of this type are phenylmethyl, 1-phenylethyl, 2-phenylethyl, (2,5-dimethylphenyl)methyl, and 4-phenyl-n-butyl.
  • R1 is alkoxycarbonylalkyl. More preferably, R1 is (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl. More preferably, R1 is ethoyxycarbonylmethyl.
  • R 6 is acyl (most preferably acetyl (ethanoyl)).
  • R 7 is hydrogen
  • alkyl refers to a saturated straight or branched hydrocarbon chain of preferably C 1 to C 6 , and specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3- methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl, and the like.
  • alkenyl refers to a branched or straight, unsaturated aliphatic group containing at least one carbon-carbon double bond which may occur at any point along the chain.
  • the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes “E” and "Z” orientations.
  • Representative examples of alkenyl groups include, but are not limited to, ethenyl, E- and Z-pentenyl, decenyl and the like.
  • Preferred alkenyl groups have 2 to 6 carbon atoms.
  • alkynyl refers to a branched or straight, unsaturated aliphatic group containing at least one carbon-carbon triple bond which may occur at any point along the chain.
  • the alkynyl radical may be optionally substituted independently with one or more substituents described herein.
  • Representative examples of alkenyl groups include, but are not limited to, ethynyl, pent-1-ynyl, and the like. Preferred alkynyl groups have 2 to 6 carbon atoms.
  • arylalkyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined above.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2- phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 2-naphth-2-ylethyl, and the like.
  • cycloalkyl refers to a saturated cyclic hydrocarbon group.
  • Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • Preferred cycloalkyl groups have 3 to 7 carbon atoms.
  • cycloalkenyl refers to a cyclic hydrocarbon group having at least one ring double bond.
  • Representative examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.
  • Preferred cycloalkenyl groups have 4 to 7 carbon atoms.
  • cycloalkylalkyl refers to a cycloalkyl group, as defined above, appended to the parent molecular moiety through an alkyl group, as defined above.
  • Representative examples of cycloalkylalkyl include, but are not limited to, cyclohexylmethyl, 2-(cyclopentyl)ethyl, 3-(cyclopropyl)propyl, 2-(cycloheptyl)ethyl, and the like.
  • cycloalkenylalkyl refers to a cycloalkenyl group, as defined above, appended to the parent molecular moiety through an alkyl group, as defined above.
  • Representative examples of cycloalkenylalkyl groups include, but are not limited to, cyclopentenylmethyl, 1-cyclohexenylethyl, 3-cycloheptenylpropyl, and the like.
  • aryl refers to aromatic monocyclic or multicyclic groups containing from 5 to 15 carbon atoms.
  • Aryl groups include, but are not limited to groups such as unsubstituted or substituted fluorenyl, unsubstituted or substituted phenyl, and unsubstituted or substituted naphthyl.
  • said substitution may be at any position on the ring, other than the point of attachment to the other ring system of a compound of the invention. Therefore, any hydrogen atom on the aryl ring may be substituted with a substituent defined by the invention.
  • the aryl is a phenyl ring
  • said substitution may be at the meta- and/or ortho- and/or para- position relative to the point of attachment. Phenyl is preferred.
  • heteroaryl refers to a monocyclic or multicyclic aromatic ring system, in certain embodiments, of 5 to 15 members where one or more, in one embodiment 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen or sulfur.
  • the heteroaryl group may be optionally fused to a benzene ring.
  • Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolinyl and isoquinolinyl.
  • heterocycle refers to a monocyclic, or bicyclic, group, having from 3 to 10 ring members, unless otherwise specified, containing 1 to 4 heteroatoms selected from N, O, S, SO, SO 2 , NH or N(C 1 -C 6 )alkyl.
  • Heterocyclic groups optionally contain 1 or 2 double bonds.
  • Heterocyclic groups include, but are not limited to, azetidinyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydro-thiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, indolinyl, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl, and benzoxazinyl.
  • heterocyclylalkyl refers to a heterocyclyl group as defined above appended to the parent molecular moiety through an alkyl group, as defined above. Examples are piperazinylmethyl, 2- piperidinylethyl and 3-morpholinylpropyl, 1-(2-furyl)-ethyl, 3-(2-imidazolyl)-propyl and the like.
  • heteroarylalkyl refers to a heteroaryl group as defined above appended to the parent molecular moiety through an alkyl group, as defined above. Examples include 2-pyridylmethyl, 3-pyridylmethyl.
  • alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, isopentoxy, neopentoxy, hexyloxy, isohexyloxy, cyclohexyloxy, 2,2-dimethylbutoxy, and 2,3-dimethylbutoxy, and the like.
  • haloalkyl refers to an alkyl as defined herein, which is substituted by one or more halo groups as defined herein.
  • the haloalkyl can be monohaloalkyl, dihaloalkyl, trihaloalkyl, or polyhaloalkyl including perhaloalkyl.
  • a monohaloalkyl can have one iodo, bromo, chloro or fluoro within the alkyl group. Chloro and fluoro are preferred.
  • Dihaloalkyl and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl.
  • haloalkyl examples include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • a perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halo atoms, e.g, trifluoromethyl.
  • acyl as used herein means an organic radical having 1 to 6 carbon atoms (branched or straight chain) derived from an organic acid by removal of the hydroxyl group.
  • acyl groups are methanoyl, ethanoyl, propanoyl, n-butanoyl, pivaloyl, and the like.
  • substituents are, unless otherwise specified, selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogen, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, nitro, cyano, and hydroxyl.
  • salts refers to salts that are known in the pharmaceutical art.
  • Compounds of the invention may be acidic or basic in nature, and hence may form salts with bases or acids respectively.
  • pharmaceutically acceptable salts are those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid.
  • salts formed with bases include metal salts such as sodium, potassium, magnesium or calcium salts or amino salts such as ammonium, triethylamine salts, and the like, all of which may be prepared according to conventional methods.
  • protecting group refers to a group that is joined to a reactive group (e.g., a hydroxyl or an amine) on a molecule.
  • the protecting group is chosen to prevent reaction of the particular radical during one or more steps of a chemical reaction.
  • the particular protecting group is chosen so as to permit removal at a later time to restore the reactive group without altering other reactive groups present in the molecule.
  • the choice of a protecting group is a function of the particular radical to be protected and the compounds to which it will be exposed. The selection of protecting groups is well known to those of skill in the art. See, for example (Wuts et al., 2014).
  • the term “protection” refers to the introduction of such a group, and the term “deprotection” to its removal.
  • protected refers to a molecule comprising such a group.
  • esters include C1-12 alkyl esters.
  • isoxazolium reagents such as those of Woodward and Kemp
  • acyloxyphosphonium reagents such as BOP, PyBOP, PyBrOP/HOBt/DIEA and TFCH
  • Protected peptidyl- ⁇ -hydroxyamide (18) is oxidized to give protected peptidyl- ⁇ -ketoamide (19).
  • Suitable oxidation conditions include Swern Oxidation, Dess-Martin's Periodinane or other methods as described (Hudlicky, 1990).
  • ⁇ -hydroxy- ⁇ -aminoamide (17) is suitably prepared by the Passerini reaction, as described (Semple et al., 2000).
  • the present compound can be administered orally or parenterally.
  • the present compound can be also used as a conventional preparation, for example, as any dosage form of a solid agent such as tablets, powders, granules, capsules and the like; an aqueous agent; an oily suspension; or a liquid agent such as syrup and elixir.
  • the present compound can be used as an aqueous or oily suspension injectable, or a nasal drop.
  • conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like may be arbitrarily used.
  • a preparation of the present invention is prepared by combining (e.g. mixing) a therapeutically effective amount of the present compound with a pharmaceutically acceptable carrier or diluent.
  • a dose of the present invention is different depending on an administration method, an age, a weight and condition n of a patient, and a kind of a disease and, usually, in the case of oral administraton, about 0.05mg to 3000mg, preferably about 0.1mg to 1000mg may be administered per adult a day, if necessary, by dividing the dose.
  • about 0.01mg to 1000mg, preferably about 0.05mg to 500mg is administered per adult per day.
  • Such a formulation will comprise the above defined compound of formula (II) together with one or more acceptable carriers or excipients and optionally other therapeutic ingredients.
  • the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.
  • the formulations include those suitable for rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration, but preferably the formulation is an orally administered formulation.
  • the formulations may conveniently be presented in unit dosage form, e.g. tablets and sustained release capsules, and may be prepared by any methods well known in the art.
  • Such methods include the step of bringing into association the above defined active agent with the carrier.
  • the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • the invention extends to methods for preparing a pharmaceutical composition
  • a pharmaceutical composition comprising bringing a compound of Formula (II) or its pharmaceutically acceptable salt in conjunction or association with a pharmaceutically acceptable carrier or vehicle. If the manufacture of pharmaceutical formulations involves intimate mixing of pharmaceutical excipients and the active ingredient in salt form, then it is often preferred to use excipients which are non-basic in nature, i.e. either acidic or neutral.
  • Formulations for oral administration in the present invention may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water in oil liquid emulsion and as a bolus etc.
  • compositions for oral administration include vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, stearic acid, glycerol stearate, silicone fluid, talc waxes, oils and colloidal silica.
  • Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring or the like can also be used. It may be used.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.
  • compositions suitable for oral administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatine and glycerine, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.
  • the compounds described herein are useful in the treatment of parasitic infections, in particular malaria. They are believed to exert such effects through their ability to inhibit the growth of or kill the parasitic protozoan which causes malaria (e.g., P. falciparum, P. vivax, P. ovale, and P. malariae).
  • the treatment may be curative, preventative or intended to arrest the progress of the disease.
  • the compounds of formula (II) may be administered with one or more known antimalarial compounds, including chloroquine, quinine, pyrimethamine, sulfadoxine, mefloquine, artemether, lumefantrine, artesunate, amodiaquine, dihydroartemisinin, piperaquine, proguanil, doxycycline, clindamycin, artemisinin, atovaquone, and any combination thereof.
  • Certain compounds of the invention may be useful in the treatment of malaria which is resistant to one or more known therapies.
  • the compounds described herein are useful in the treatment of Parkinson's disease.
  • the treatment may be curative, preventative or intended to arrest the progress of the disease.
  • the compounds of formula (II) may be administered with one or more known compounds for this indication, including L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine.
  • the compounds of the invention are useful in the treatment of cancer.
  • Exemplary cancers that may be treated by the compounds and methods of the invention include, but are not limited to, myeloid leukemia, lymphoblastic leukemia, melanoma, breast, lung, colon, liver, gastric, kidney, ovarian, uterine, and brain tumours.
  • the compounds of the invention are effective in lowering glucose, lipids, and insulin in diabetic animals and lipids in non-diabetic animals.
  • the compounds are efficacious in the treatment, control and/or prevention of non-insulin dependent diabetes mellitus (NIDDM) in humans and in the treatment, control, and/or prevention of conditions associated with NIDDM.
  • NIDDM non-insulin dependent diabetes mellitus
  • the compounds of the invention are effective in treating bacterial infections in animals including man, which comprises administering to the afflicted animals an antibacterially effective amount of a compound or a pharmaceutical composition of a compound of the invention.
  • the compounds of the invention are useful to treat bacterial infections including infections caused by Gram- negative bacterial strains, Gram-positive bacterial strains and multiple drug- resistant bacterial strains.
  • Gram-negative bacterial strains include Escherchia coli, Caulobacter crescentus, Pseudomonas aeruginosa, Agrobacterium tumefaciens, Branhamella catarrhalis, Citrobacter diversus, Enterobacter aerogenes, Enterobacter cloacae, Enterobacter sakazakii, Enterobacter asburiae, Pantoea agglomerans, Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella rhinoscleromatis, Proteus mirabilis, Salmonella typhimurium, Salmonella enteriditis, Serratia marcescens, Shigella sonnei, Neisseria gonorrhoeae, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter Iwoffi, Fusobacterium nucleatum, Veillonella parvula, Bacteroides forsythus, Act
  • Gram-positive bacterial strains include Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pyogenes, Streptococcus faecalis, Enterococcus faecalis, Enterococcus faecium, Bacillus subtilis, Bacillus anthracis, Bacillus cereus, Micrococcus luteus, Mycobacterium tuberculosis, Clostridium difficile, Propionibacterium acnes, Streptococcus mutans, Actinomyces viscosus, Actinomyces naeslundii, Streptococcus sanguis, Streptococcus pneumoniae, Streptococcus viridans and Streptococcus salivarius.
  • Multiple drug-resistant bacterial strains include methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococci, multiple drug-resistant Mycobacterium tuberculosis, and multidrug-resistant Clostridium difficile.
  • N-substituted peptidyl- ⁇ -ketoamides were synthesised in four stages using published methods:
  • Trifluoroacetate ester was detected in most of the cases. It was removed by hydrolysis with 4 M NaOH added to a methanol solution of the crude product at r.t., according to HPLC control. Then methanol was evaporated and the residue was dissolved in ethylacetate and was washed with NaHCO 3 saturated aqueous solution (2 x), 10 % KHSO 4 (2x) and brine (1x). The ethylacetate layer was dried over MgSO 4 , filtered off and evaporated, giving the crude product. The product can be purified by RP-HPLC chromatography, if necessary.
  • the product was purified by preparative RP-HPLC, using gradient 15 - 50% B on 250 ⁇ 21 mm C18 column.
  • the protected peptide (1 eqv) has been activated in DMF solution (0.8 ml) by the consequent addition of TCFH (1.2 eqv) and DIEA (1.7 eqv) 2-3 min prior to the coupling. Then H 2 N-CH(CH 3 )- CH(OH)-CONHX. HCl have been added (2 eqv) as a solution in 0.5 ml DMF. DIEA (1.6 eqv) was added at the end. The mixture was stirred overnight at room temperature. pH of the reaction mixture must be basic. The DMF was evaporated and the oil-like product was triturated with 10 % KHSO 4 till the pale-yellow precipitate was formed. It was washed on a sintered glass with 10 % KHSO 4 and water. The product was dried in vacuo. The following products were synthesized:
  • reaction mixture was diluted with EtOAc (40 x), washed with aq.NaHCO 3 (2x), 10 % KHSO 4 (2x) and water (1 x). The combined ethylacetate layers were dried over MgSO 4 , filtered off and evaporated, giving the crude product.
  • the unsubstituted ketoamide has been synthesized by transforming the aldehyde moiety of the Boc- protected P1 aminoaldehyde formed in step (2) to a cyanhydrin and subsequent partial hydrolysis of the cyanide moiety to an amide (Venkatraman et al., 2006).
  • amino acid sequences in compounds 1-15 correspond to SEQ ID NO. 1 and to SEQ ID NO. 2.
  • the most effective compounds show inhibitory constants against the model rhomboid protease GlpG between 10 and 100 nM.
  • the in vivo activity of the compounds against GlpG according to the invention is in the low nanomolar range ( Fig. 1 ), which is up to three orders of magnitude better than any other currently used rhomboid inhibitors.
  • the co-crystal structures of these compounds with rhomboid protease ( Fig. 2 ) show their mode of binding into the active site of rhomboid. Without wishing to be bound by such a theory, it appears that the ketoamide warhead covalently bonds to the catalytic serine, and extensively hydrogen bonds throughout the active site.
  • the present inventions can be used in pharmaceutical industry. Namely, the described variations of peptidyl ketoamide inhibitors can be used as tools in cell-biological studies or as lead compounds in drug development against rhomboid proteases, in particular but not limited to the disease contexts of malaria, Parkinson's disease, cancer, diabetes or infections by pathogenic Escherichia coli or related bacteria.

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Claims (9)

  1. Un composé de formule (II)
    Figure imgb0066
    dans laquelle R1 est choisi dans le groupe constitué de H, alkyle, haloalkyle, alcényle, alcynyle, aryle, arylalkyle, cycloalkyle, cycloalkylalkyle, cycloalcényle, cycloalcénylalkyle, hétérocyclyle, hétérocyclylalkyle, hétéroaryle et hétéroarylalkyle, chacun facultativement substitué par 1 à 3 substituants choisis indépendamment dans le groupe constitué d'alkyle, cyano, halo, oxo, nitro, hydroxyle, -O(alkyle), -NH2, -N(H)(alkyle), -N(alkyle)2, -S(alkyle), -S(O)(alkyle), -SO2alkyle, -NHCONH2, -CO2H, -CO2(alkyle), -COalkyle, -CONH2, -CONHalkyle et -CON(alkyle)2;
    R2 et R5 sont choisis parmi hydrogène et alkyle;
    R3 est un alkyle en C1-C6;
    R6 est un acyle, où le terme « acyle » tel qu'utilisé ici signifie un radical organique ayant 1 à 6 atomes de carbone (chaîne ramifiée ou droite) dérivé d'un acide organique par élimination du groupe hydroxyle;
    R7 est l'hydrogène;
    W représente un groupe choisi parmi -Arg-His, -Trp-His, -Val-Arg-His, -Val-Trp-His, -Arg-Val-Arg-His (SEQ ID NO. 1) et -Arg-Val -Trp-His (SEQ ID NO. 2);
    ou un sel ou ester pharmaceutiquement acceptable de celui-ci.
  2. Composé selon la revendication précédente, dans lequel R1 est choisi dans le groupe constitué par alkyle, cycloalkyle, arylalkyle éventuellement substitué sur le cycle aryle par de 1 à 3 substituants alkyle en C1-C3, et alcoxycarbonylalkyle.
  3. Composé selon l'une quelconque des revendications précédentes, dans lequel R6 est un acétyle.
  4. Composé selon la revendication 1 qui est l'un des
    Figure imgb0067
    Figure imgb0068
    Figure imgb0069
    Figure imgb0070
    Figure imgb0071
    Figure imgb0072
    Figure imgb0073
    Figure imgb0074
    Figure imgb0075
    Figure imgb0076
    Figure imgb0077
    Figure imgb0078
    Figure imgb0079
    Figure imgb0080
    Figure imgb0081
  5. Composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 4 avec un excipient pharmaceutiquement acceptable.
  6. Composé selon l'une quelconque des revendications 1 à 4 ou composition pharmaceutique selon la revendication 5 pour une utilisation en thérapie.
  7. Composé selon l'une quelconque des revendications 1 à 4 ou composition pharmaceutique selon la revendication 5 pour une utilisation dans le traitement d'un état choisi parmi le paludisme, le cancer, la maladie de Parkinson, le diabète et une infection bactérienne.
  8. Procédé d'inhibition de l'activité d'une protéase rhomboïde présente dans une cellule in vitro, comprenant la mise en contact de ladite cellule avec une quantité efficace du composé selon la revendication 1.
  9. Procédé selon la revendication 8, dans lequel la protéase rhomboïde est GlpG.
EP18734418.9A 2017-06-12 2018-06-12 Peptidyl-cétoamides utilisés en tant qu'inhibiteurs de protéases rohomboïdes Active EP3638686B1 (fr)

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HRP20211981TT HRP20211981T1 (hr) 2017-06-12 2018-06-12 Peptidil ketoamidi kao inhibitori romboidnih proteaza
SI201830508T SI3638686T1 (sl) 2017-06-12 2018-06-12 Peptidil ketoamidi kot inhibitorji romboidnih proteaz

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US5763576A (en) * 1995-10-06 1998-06-09 Georgia Tech Research Corp. Tetrapeptide α-ketoamides
HU227742B1 (en) * 1996-10-18 2012-02-28 Vertex Pharma Inhibitors of serine proteases, particularly hepatitis c virus ns3 protease
JP2001508418A (ja) * 1996-12-27 2001-06-26 ベーリンガー インゲルハイム（カナダ）リミテッド ヒトサイトメガロウイルスプロテアーゼのペプチドミメティックインヒビター
GB9812523D0 (en) * 1998-06-10 1998-08-05 Angeletti P Ist Richerche Bio Peptide inhibitors of hepatitis c virus ns3 protease
US6649593B1 (en) * 1999-10-13 2003-11-18 Tularik Inc. Modulators of SREBP processing
CN103145608B (zh) * 2011-12-07 2015-09-02 南开大学 抗肠病毒71(ev71)己内酰胺类化合物及其制备方法和用途

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